Year : 2000 | Volume
: 11 | Issue : 4 | Page : 537--542
An Update on the Hemolytic Uremic Syndrome
Bernard S Kaplan
Department of Pediatrics, The Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Bernard S Kaplan
The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania, 19104
|How to cite this article:|
Kaplan BS. An Update on the Hemolytic Uremic Syndrome.Saudi J Kidney Dis Transpl 2000;11:537-542
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Kaplan BS. An Update on the Hemolytic Uremic Syndrome. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2020 Jul 11 ];11:537-542
Available from: http://www.sjkdt.org/text.asp?2000/11/4/537/36639
Recent major outbreaks in several parts of the world of Escherichia coli enteritis with subsequent development of hemolytic uremic syndrome (HUS), continue to draw attention to this important public health problem. In August 1998, Time Magazine featured Escherichia coli, as the killer germ on its front cover and there are many reports about this problem in the medical literature and lay media in recent years. HUS is not a notifiable disease in every state of the United States. However, although 63 cases of post-diarrheal HUS were reported to the National Center for Infectious Diseases for the first 36 weeks of 1999, it is estimated that there are about 1000 new cases of HUS in the United States each year. The purpose of this review is to present recent developments in the understanding of HUS and to re-emphasize the fact that HUS differs in important respects from thrombotic thrombocytopenic purpura (TTP).
Shiga toxin-associated HUS (Stx HUS)
The term Stx HUS is more precise than D+, typical or post-diarrheal HUS. Stx HUS follows infection with shiga toxin-producing bacteria that include Escherichia coli (STEC) and Shigella dysenteriae type 1. Stx HUS is a post-infectious, multi-system syndrome defined by acute onset of hemolytic anemia with fragmented erythrocytes, thrombocytopenia and renal injury. 
There is still an unfortunate inclination on the part of nephrologists and hematologists in internal medicine to 'diagnose' TTP in adult patients who have Stx HUS. Any patient, who develops acute onset of hemolytic anemia with fragmented erythrocytes, thrombocytopenia and renal injury, following an episode of bloody diarrhea, whether a child or an adult, whether there is a fever or not, and whether or not there is central nervous system involvement, has HUS and not TTP. This cannot be stressed strongly enough because of the implications for treatment and prognosis.
Stx HUS usually follows gastroenteritis with bloody diarrhea but occasionally can occur with non-bloody diarrhea and may rarely complicate a urinary tract infection. Stx HUS must be anticipated in any patient with bloody diarrhea. It must be suspected in any patient with diarrhea whose urine volume does not increase when adequate hydration is restored, or who becomes pale or edematous during or after an episode of bloody diarrhea. It must also be suspected in any patient who has seizures during or after bloody diarrhea. Stx HUS occurs in all ages but mainly between six months and four years. Slightly more females are affected. It occurs mainly in summer, as sporadic cases and in epidemics. Epidemics have been caused by ingestion of undercooked ground meat contaminated with Escherichia coli 0157:H7. Ground meat must be cooked to a temperature of more than 68°C (155°F). HUS also follows ingestion of contaminated fruit, vegetables, water, apple cider, milk-containing products, and many different kinds of undercooked and prepared meats. Affected cases must be reported to the appropriate health department and contacts that develop diarrhea must be evaluated medically. The incubation period is one to ten days. Five to 15% of children with Escherichia coli 0157:H7 gastrointestinal infections are at risk for HUS. Antibiotics increase the risk of developing Stx HUS after Escherichia coli 0157:H7 infection.  Among 71 children with Escherichia coli O157:H7 diarrhea, HUS developed in five of nine who were treated with antibiotics (56 percent). In contrast, HUS developed in only five of the 62 children who had not been treated with antibiotics (8 percent).  Similarly, antimotility agents should not be used to treat suspected Escherichia coli 0157:H7 gastroenteritis. The importance of washing hands, cooking meat well, avoiding contamination of food by uncooked meat, and eating only pasteurized dairy products, cannot be over emphasized. In addition, toddlers with diarrhea must be prevented from attending day-care schools and swimming in pools.
New observations, and references, on the pathogenesis of Stx HUS can be found in references 3 and 4. STEC colonize the intestine, produce Stx1 and Stx2, and these translocate across the intestinal epithelium. Stx1 and 2 have A and B subunits. The A subunit has N-glycanase activity and the five B subunits bind to the globotriaosylceramide (Gb3) receptor. It is not known whether Stx is released in single or multiple waves. Stx-induced endothelial cell damage still appears to be the central event in the pathogenesis of renal dysfunction and injury in Stx HUS. Glomerular endothelial cells become swollen and detach from the underlying basement membrane. As a result of the injury there are abnormalities in the procoagulant and anticoagulant functions of the endothelial cells. Cytokines and lipopolysaccharide amplify Stx sensitivity. Stx stimulates the procoagulant, thromboxane A2. Activation of human endothelium by tissue necrosis factor (TNF) or IL-1 after exposure to Stx, increases Gb3 synthesis, and increases the expression of functional Gb3 receptor.
Endothelial cells are not the only targets for Stx in the kidney. Other renal cells have receptors for Stx and are damaged by this toxin. Stx directly injures human proximal tubular cells in vitro. Distal renal tubular cells express Gb3 and undergo apoptosis after exposure to Stx. Stx1 and Stx2 were found in tubular epithelial cells of a patient with Stx HUS. Gb3 is expressed on cultured human mesangial cells and it is noteworthy that these cells are also injured in patients with Stx HUS. The damage varies from mild cellular edema to severe mesangiolysis. Inhibition of protein synthesis by Stx1 is potentiated by preincubation of the cells with IL-1 or TNF-alpha. These cytokines activate chemokine genes and result in lethal toxic injury. Recent studies show that human glomerular epithelial cells (human GEC) express Gb3 and are susceptible to the toxic effects of Stx1.  The effects of Stx1 are amplified by exposure to proinflammatory IL-1, TNF, LPS and butyrate. In summary, Stx has toxic effects on renal arteriolar and glomerular endothelial cells, aortic, and brain endothelial cells, mesangial cells, proximal and distal renal tubular epithelial cells, monocytes, astrocytoma cells, lung epithelial cells, glomerular epithelial cells and direct effects on polymorphonuclear cells. Erythrocytes and platelets may also have receptors for Stx.
Stx HUS is a multi-system disease that can affect the gastrointestinal tract, kidneys, blood, brain, pancreas, liver, heart and lungs. The serious immediate consequences include colonic gangrene, acute renal failure, minor to severe cerebral impairment, and transient or permanent diabetes mellitus. Acute hepatic injury, cardiac failure or adult respiratory distress syndrome is less often seen. Conservative treatment with appropriate use of peritoneal or hemodialysis, maintenance of fluid and electrolyte balances, careful control of hypertension, and judicious use of blood transfusions has reduced the acute mortality rate from as high as 30% to below 3%. Platelet infusions should not be given unless there is active bleeding or a surgical procedure is required. There are no advantages for the use of fresh frozen plasma, plasmapheresis, anticoagulants or anti-platelet agents. Trials on the use of Synsorb Pk to prevent HUS or to reduce its effects are still in progress. 
Renal biopsies are rarely indicated. The diagnosis of colonic gangrene and the prevention and treatment of central nervous system injury remain areas of major difficulty. Few children with Stx HUS progress to chronic dialysis or require renal transplantation.  The outcome in elderly adults remains more guarded, in part because of co-morbid conditions. Most patients who have normal serum creatinine concentrations, normal blood pressures and no proteinuria a year after the acute episode, have an excellent long-term prognosis.  Long-term serious sequelae are surprisingly infrequent and include chronic renal failure, diabetes mellitus, cholecystitis,  and very rarely, central nervous system impairment. Less serious renal sequelae include mild to moderate reductions in glomerular filtration rate, proteinuria, and hypertension. Posttransplant recurrences of Stx HUS are extremely rare and there is no contraindication to using inhibitors of calcineurin. 
Idiopathic (atypical or non-diarrheaassociated) HUS is a heterogeneous yet distinct subgroup of the HUS that differs from diarrhea-associated HUS on epidemiologic, clinical, laboratory, histologic, and prognostic grounds.  Some of these patients have hypocomplementemia with low Factor H concentrations and the pathogenesis may be linked to disorders of complement. , Treatment can be extremely difficult because of severe hypertension, parental anxiety about the possibility of recurrences, and course that is often indolent. Plasmapheresis, although unproven, is still recommended. Posttransplant recurrences are frequent. Using a living-related kidney and calcineurin antagonists increase the chances of a recurrence, whereas pretransplant nephrectomies may reduce the possibility of a recurrence  .
Autosomal recessive and autosomal dominant inheritance of HUS
A diagnosis of autosomal recessive or autosomal dominant HUS cannot be made in the absence of a positive family history.  However, it must be suspected in patients who have idiopathic HUS especially if there is hypocomplementemia and a Factor H deficiency. In the recessive form there are no recognized precipitating events, and no sex or race preferences. Most affected individuals have been infants and children, but adults are not exempt. In occasional patients there may be complete resolution, in some there may be several episodes of HUS, and HUS may recur before and/or after renal transplantation. 
Pregnancy may be a precipitating event in the dominant form in which adults are affected more often than children; there is no sex or race preference.  Complete recovery is uncommon. The pathogenesis of the inherited forms of HUS is being elucidated with new insights into the possible role of Factor H deficiency and evidence of linkage to the Factor H locus on chromosome 1. , There is no specific treatment but fresh frozen plasma infusions and plasmapheresis are indicated for inherited cases. The prognosis is dismal for renal and poor for patient survival. The timing of a renal transplant presents problems, but it is advisable to wait for six to twelve months between the occurrence of HUS and the transplant. The patient must be free from all evidence of active disease. Although the use of a living-related donor presents a problem, there are no definite guidelines. There are also no hard data in regard to the use of cyclosporin A or oral contraceptives. Pregnancy may increase the likelihood of recurrences. Genetic counseling is particularly difficult if the patient is the first affected individual in the family.
Thrombotic thrombocytopenic purpura (TTP)
It has become abundantly clear that Stx HUS differs fundamentally from TTP in regard to etiology, pathogenesis and outcome. Therefore, the term HUS/TTP is best avoided because it confuses the approach to diagnosis, treatment and outcome. An increasing body of evidence demonstrates perturbations in the function of von Willibrand factor (vWf) proteases in TTP.  Two different defects have been demonstrated. Patients with acute TTP had a severe deficiency of vWf-cleaving protease caused by inhibitory activity against the protease.  No deficiency was detected in patients in TTP who were in remission. The inhibitors were IgG antibodies and the resultant deficiency of this protease may have a role in the pathogenesis of platelet thrombosis in TTP.  Patients with familial forms of TTP lacked vWf-cleaving protease activity but had no inhibitor.  These findings are in contrast to those in HUS where patients with inherited HUS had normal or slightly decreased levels of activity of vWf-cleaving protease during the acute episode.  Furthermore, in vitro proteolytic degradation of vWf by the protease was normal in all patients with inherited HUS and non-inherited HUS. ,
Therefore, non-familial TTP appears to result from an inhibitor of vWf-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Furthermore, patients with TTP have a deficiency of vWf-cleaving protease, whereas patients with HUS have normal activity of this protease. , The ability of plasmapheresis to remove autoantibodies to the vWf-cleaving protease provides the first solid rationale for this treatment in some patients with TTP.
Recent studies have demonstrated that TTP may be caused by the antiplatelet agents ticlopidine  and clopidogrel.  Autoantibodies to the vWF metalloproteinase were demonstrated in patients who developed ticlopidine-associated TTP; this led to the same type of vWF abnormalities observed in patients with idiopathic acute TTP. The findings suggest that failure to process large and unusually large vWF multimers in vivo caused binding of vWF to platelets, systemic platelet thrombosis, and TTP.
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